As a rule, esophageal adenocarcinoma develops in the lower esophagus. Life expectancy and survival rates depend on the cancer stage and the general health of the patient. Chemoradiotherapy is the most successful treatment approach to this type of cancer. The choice of optimal radiation doses for achieving the best possible therapeutic effect is still a challenge. The aim of this paper was to study effective radiation doses and assess response of human esophageal adenocarcinoma to radiation using a PDX model. The study was conducted in female Balb/c nude mice (n = 25). Fragments of the donor tumor were implanted into the cervical esophagus of immunodeficient mice. Effects of radiation on the obtained orthotopic xenografts were studied after each of 3 irradiation sessions (4, 6, 8, and 10 Gy in each of the experimental groups, respectively). First-passage xenografts reproduced the morphology of the donor tumor. The mean tumor volume differed significantly between the control group and the experimental groups exposed to 6, 8 or 10 Gy (р ≤ 0.01) after each irradiation session. Tumor growth delay was significant after exposure to the total dose of 18 Gy. The further radiation dose increase was ineffective. The reduction of tumor volume in the xenografts was correlated to the increase in the one-time radiation dose. The total dose over 18 Gy produced a detrimental effect on the hematopoietic system and blood biochemistry of the experimental mice.